Project 2: 'Smart'Nanoparticles for Cancer Therapy and Imaging The overall goal of Project 2 is to stringently evaluate the potential of 'smart'nanoparticles in cancer therapy and imaging. This project will be closely linked to Project 1 and will primarily utilize nanoparticles fabricated by the PRINT technology described therein. A variety of nanoparticle sizes, shapes and chemical compositions will be tested. The nanoparticles will contain standard antitumor drugs, therapeutic siRNA or antisense oligonucleotides, or imaging agents. The delivery capabilities of the nanoparticles will be examined in challenging murine tumor models having diverse biological characteristics including B-cell lymphomas, melanomas, and breast, prostate, and pancreatic carcinomas. In some instances tumor delivery will reflect the ability of long-circulating nanoparticles to preferentially extravasate across 'leaky'tumor vasculature. In other cases cell-targeting ligands will be linked to the nanoparticles;generation of the targeting ligands will involve the Combinatorial Library Research Core of the C-CCNE. Targets for these ligands include the HER2 and TVA receptors on models of breast and pancreatic tumors. The ability of nanoparticles to access tumors will be evaluated by incorporating MRI or X-ray contrast agents and by using the Small Animal Imaging Core. Other studies will test the impact on tumor growth and progression of therapeutic moieties delivered via nanoparticles. Initial studies in this project will be fed back into Project 1 to guide the development of further generations smart nanoparticles that will then be tested in turn in the several animal tumor models. This cycle is intended to promote the rapid development of nanocarriers effective in cancer diagnosis and therapy.